Peter J. Späth
University of Bern
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Allergy | 2003
Hans-Uwe Simon; Peter J. Späth
Intravenous immunoglobulin (IVIG) preparations are fractionated from a plasma pool of several thousand donors. IVIG contain immune antibodies and physiologic autoantibodies. Immune antibodies reflect the immunologic experience of the donor population. This fraction of IVIG preparations is useful for replacement therapy and passive immunisation. Natural autoantibodies are able to react with the immune system of the recipient of IVIG and are suggested to help to correct immune deregulation. Immunomodulatory and anti‐inflammatory properties are based on multiple mechanisms of action which are described. These mechanisms are effective concomitantly and synergistically at every occasion of use of IVIG in inflammatory and autoimmune disorders.
European Journal of Pediatrics | 2012
Volker Wahn; Werner Aberer; Wolfgang Eberl; Maria Faßhauer; Thomas Kühne; Karin Kurnik; Markus Magerl; Dirk Meyer-Olson; Inmaculada Martinez-Saguer; Peter J. Späth; Petra Staubach-Renz; Wolfhart Kreuz
Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.
Frontiers in Immunology | 2014
Jacqueline Kerr; Isabella Quinti; Martha Eibl; Helen Chapel; Peter J. Späth; W. A. Carrock Sewell; Abdulgabar Salama; Ivo N. van Schaik; Taco W. Kuijpers; Hans-Hartmut Peter
The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic “per kg” dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki’ disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases.
Frontiers in Immunology | 2015
Peter J. Späth; Guido Granata; Fabiola La Marra; Taco W. Kuijpers; Isabella Quinti
Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.
Clinical Reviews in Allergy & Immunology | 2005
Nicola Boschetti; Martin Stucki; Peter J. Späth; Christoph Kempf
Patients with immunodeficiencies or some types of autoimmune diseases are dependent on safe therapy with intravenous immunoglobulins. State-of-the-art manufacturing processes provide a high safety standard by incorporating virus elimination procedures into the manufacturing process. Based on their mechanism, these procedures are grouped into three classes: partitioning, inactivation, and removal based on size.Because of current socioeconomic and ecological changes, emerging pathogens continue to be expected. Such pathogens may spread very quickly because of increased intercontinental traffic. Severe acute respiratory syndrome-coronavirus and the West Nile virus are recent examples. Currently, it is not possible to predict the impact such a pathogen will have on blood safety because the capacity for a globally coordinated reaction to such a threat is also evolving.The worst-case scenario would be the emergence of a transmissible, small, nonenveloped virus in the blood donor population. Examples of small nonenveloped viruses, which change host and tissue tropism, are discussed, with focus on parvoviridae.Although today’s immunoglobulins are safer than ever, in preparation for future challenges it is a high priority for the plasma industry to proactively investigate such viruses on a molecular and cellular level to identify their vulnerabilities.
Expert Opinion on Pharmacotherapy | 2012
Delphine Charignon; Peter J. Späth; Ludovic Martin; Christian Drouet
Introduction: HOE-140/Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. Areas covered: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin–receptor interactions. Expert opinion: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.
PLOS ONE | 2014
Makoto Sudo; Yoshiki Yamaguchi; Peter J. Späth; Kana Matsumoto-Morita; Benjamin K. Ong; Nortina Shahrizaila; Nobuhiro Yuki
Intravenous immunoglobulin (IVIG) is the first line treatment for Guillain–Barré syndrome and multifocal motor neuropathy, which are caused by anti-ganglioside antibody-mediated complement-dependent cytotoxicity. IVIG has many potential mechanisms of action, and sialylation of the IgG Fc portion reportedly has an anti-inflammatory effect in antibody-dependent cell-mediated cytotoxicity models. We investigated the effects of different IVIG glycoforms on the inhibition of antibody-mediated complement-dependent cytotoxicity. Deglycosylated, degalactosylated, galactosylated and sialylated IgG were prepared from IVIG following treatment with glycosidases and glycosyltransferases. Sera from patients with Guillain–Barré syndrome, Miller Fisher syndrome and multifocal motor neuropathy associated with anti-ganglioside antibodies were used. Inhibition of complement deposition subsequent to IgG or IgM autoantibody binding to ganglioside, GM1 or GQ1b was assessed on microtiter plates. Sialylated and galactosylated IVIGs more effectively inhibited C3 deposition than original IVIG or enzyme-treated IVIGs (agalactosylated and deglycosylated IVIGs). Therefore, sialylated and galactosylated IVIGs may be more effective than conventional IVIG in the treatment of complement-dependent autoimmune diseases.
Journal of Immunological Methods | 2001
Emiliana Jelezarova; Markus Schlumberger; Salima Sadallah; Peter J. Späth; Jürg A. Schifferli; Hans U. Lutz
C3 nephritic factor (C3NeF) is an autoantibody against the C3 convertase which stabilizes this otherwise inherently labile neoenzyme and induces a continuous activation of the alternative pathway with C3 depletion. NeF is found in patients with membranoproliferative glomerulonephritis and/or partial lipodystrpohy. NeF activity is usually detected in plasma by hemolytic tests. In order to obtain reproducible data for the functional activity of purified C3NeF IgG a solid phase assay was developed. C3 convertase was generated on immobilized C3b by incubation with factors B and D in the presence of Ni(2+). Convertase sites were left to decay in the presence of normal IgG or NeF IgG. Residual convertase activity was measured by adding 125I-C3 and capturing nascent 125I-C3b on the plate surface via covalently coupled NH2-Glu-Tyr dipeptide. In the presence of factor H during C3 convertase decay, a dose dependent stabilizing activity was shown for NeF IgG including NeF IgG purified from urine. A second format of the assay was developed in which C3 convertase was assembled on C3b(2)-IgG complexes in the presence of Mg(2+). Since these complexes are more efficient as convertase precursors the signal was five-fold higher than with C3b. Convertase decay, on the other hand, was not influenced by the nature of the precursor and in both systems the stabilizing activity of NeF IgG was similar.
Clinical and Experimental Immunology | 2009
Eduardo Fernández-Cruz; Srini V. Kaveri; H. H. Peter; Anne Durandy; N. Cantoni; Isabella Quinti; Ricardo U. Sorensen; J. B. Bussel; Maria Giovanna Danieli; A. Winkelmann; Jagadeesh Bayry; Fabian Käsermann; Peter J. Späth; M. Helbert; Abdulgabar Salama; I. N. van Schaik; N. Yuki
The posters presented at the 6th International Immunoglobulin Symposium covered a wide range of fields and included both basic science and clinical research. From the abstracts accepted for poster presentation, 12 abstracts were selected for oral presentations in three parallel sessions on immunodeficiencies, autoimmunity and basic research. The immunodeficiency presentations dealt with novel, rare class‐switch recombination (CSR) deficiencies, attenuation of adverse events following IVIg treatment, association of immunoglobulin (Ig)G trough levels and protection against acute infection in patients with X‐linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVID), and the reduction of class‐switched memory B cells in patients with specific antibody deficiency (SAD). The impact of intravenous immunoglobulin on fetal alloimmune thrombocytopenia, pregnancy and postpartum‐related relapses in multiple sclerosis and refractory myositis, as well as experiences with subcutaneous immunoglobulin in patients with multi‐focal motor neuropathy, were the topics presented in the autoimmunity session. The interaction of dendritic cell (DC)‐SIGN and α2,6‐sialylated IgG Fc and its impact on human DCs, the enrichment of sialylated IgG in plasma‐derived IgG, as wells as prion surveillance and monitoring of anti‐measles titres in immunoglobulin products, were covered in the basic science session. In summary, the presentations illustrated the breadth of immunoglobulin therapy usage and highlighted the progress that is being made in diverse areas of basic and clinical research, extending our understanding of the mechanisms of immunoglobulin action and contributing to improved patient care.
Advances in Experimental Medicine and Biology | 2012
Peter J. Späth; Hans Lutz
It was a long way from the use of hyperimmune animal sera for the treatment of toxin-producing infections to the production of polyclonal, polyspecific human immunoglobulin preparations and the use of NAbs as therapeutic tools for autoimmune and inflammatory diseases. Some highlights of the development of knowledge in blood fractionation techniques, basic science and clinical wisdom are reviewed in this chapter. Proudly we mention the outstanding contribution of Swiss scientists and clinicians in the development of IVIG as clinical tool for some otherwise untreatable diseases or taking advantage of its low adverse event profile in long-term treatment of other chronic autoimmune and inflammatory diseases. This chapter summarizes some of the characteristics and the effects in humans of NAbs which are present in IgG concentrates. We call attention to the fact that the human data remain, at least in part, incomplete, among others because even with the most efficient large-scale techniques available not more than approximately 50% of the total IgG in plasma can be fractionated into an immunoglobulin G concentrate.